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Drug Criteria & Outcomes: Ramipril formulary evaluation
By Annie Allen,
Written while on clinical rotation with
Auburn University at Huntsville (AL) Hospital
Ramipril (Altace) is a long-acting oral angiotensin-converting enzyme (ACE) inhibitor indicated for the treatment of patients with essential hypertension or congestive heart failure after myocardial infarction. Ramipril also is indicated in cardiovascular risk reduction. Ramipril is the ethyl ester of a non-sulfhydryl ACE inhibitor.1
Mechanism of action
Ramipril is a prodrug that is metabolized to the active form ramiprilat. Like other members of the ACE inhibitor class, ramiprilat lowers blood pressure, primarily through the inhibition of ACE. This results in decreased plasma angiotensin II, leading to decreased vasopressor activity, decreased aldosterone secretion, and increased plasma renin activity.2
The Food and Drug Administration (FDA)-approved indications for ramipril include hypertension, congestive heart failure post-myocardial infarction, and cardiovascular risk reduction. Some data suggest that ramipril is more effective than some other ACE inhibitors because it has higher tissue concentrations and thus better inhibition of tissue ACE. However, the data are not conclusive in this area. Other ACE inhibitors thought to have high levels of tissue ACE inhibition include enalapril and fosinopril. The non-prodrug ACE inhibitors, captopril and lisinopril, are not thought to have high tissue concentrations because of their low lipophilicity. The FDA indications for ramipril as compared to the ACE inhibitors included on the Huntsville (AL) Hospital formulary are shown in Table 1, below.3
The extent of absorption of ramipril is at least 50-60% and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced. In a trial in which subjects received ramipril capsules or their contents dissolved in water or apple juice or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or nonuse of concomitant liquid or food.2
During 24-hour continuous ambulatory blood pressure monitoring, at least 50% of the maximal response of ramiprilat is maintained for 24 hours. Blood pressure was lower by a mean of 6/4 mmHg compared to placebo at the end of the dosing interval.1 Therefore, ramipril is acceptable for once-daily dosing.
Ramipril is hydrolyzed by hepatic esterases to its active metabolite, ramiprilat. Glucuronidation and hydroxylation reactions are responsible for forming the six other inactive metabolites of ramipril. Plasma ramiprilat concentrations peak at two to four hours after drug intake and then decline in a triphasic manner. The initial rapid decline represents distribution of the drug into a large peripheral compartment and subsequent binding to plasma and tissue ACE with a half-life of two to four hours. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of nine to 18 hours. The terminal elimination phase has a prolonged half-life (greater than 50 hours) and represents potent binding to ACE with slow dissociation from the enzyme, and does not contribute to accumulation of the drug.2 About 70% of ramipril and its metabolites are cleared renally, with the remaining 30% eliminated by hepatic mechanisms.3 About 73% of circulating ramipril and 56% of ramiprilat is bound to plasma proteins; therefore, drug interactions due to protein binding are not expected.
Ramipril’s area under the curve (AUC) increases with decreasing renal function. In patients with creatinine clearance of less than 40 mL/min, the AUC is three to four times greater than in patients with normal renal function. Therefore, dose adjustment is required in renal impairment. Plasma ramipril levels in patients with impaired liver function are increased about three-fold. Peak concentrations of ramiprilat are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.2
The pharmacokinetics of ramipril as compared to the ACE inhibitors on the Huntsville Hospital formulary are shown in Table 2, below.3
All ACE inhibitors have similar efficacy in the treatment of mild-to-moderate hypertension when given in equipotent doses. There are several clinical trials comparing the efficacy of ramipril to that of other ACE inhibitors, and ramipril appears to be as effective as other ACE inhibitors. Ramipril is effective for the treatment of mild-to-moderate essential hypertension as shown by the summary of clinical trials below.
Ramipril was evaluated in 591 patients with essential hypertension in a multicenter, open-label, prospective trial. Patients received 1.25-10 mg of ramipril once daily for eight weeks.4 Results of the study showed that ramipril reduced mean systolic/diastolic blood pressure by 19.9/14.7 mmHg (P < 0.001/P < 0.001) when compared with baseline blood pressure, and ramipril reduced diastolic blood pressure to < 90 mmHg or by at least 10 mmHg in 84.1% of patients. Response rates were similar regardless of age, gender, or race, and no patient stopped ramipril because of an adverse event or experienced an unexpected adverse event. This study shows that ramipril is effective in lowering blood pressure, but the results would be more meaningful if the effects of ramipril were compared to the effects of a placebo.
In a randomized, double-blind trial, ramipril was compared with placebo in the treatment of 86 patients with mild-to-moderate essential hypertension.5 A two-week placebo run-in phase was followed by four weeks of treatment. Patients receiving ramipril 5 mg had significantly larger decreases in blood pressure than patients receiving placebo (P < 0.001).
A 16-week randomized, double-blind trial in 248 patients showed ramipril once daily to be as effective and well-tolerated as captopril twice daily for the treatment of hypertension.6 After a four-week placebo run-in period, patients with a supine and standing diastolic blood pressure between 95 and 120 mmHg were randomized to treatment with ramipril 10 mg once daily or captopril 50 mg twice daily. Patients not responding to therapy after six weeks received 50 mg hydrochlorothiazide concomitantly. After six weeks of therapy, mean supine pressure was reduced significantly by both ramipril and captopril. A further reduction of 7/6 mmHg in the ramipril group and 6/6 mmHg in the captopril group occurred with six additional weeks of treatment. Reductions in standing blood pressure were similar. Forty patients in the ramipril group and 36 in the captopril group required the addition of hydrochlorothiazide. After 12 weeks of active treatment, 77% and 83% of patients in the ramipril and captopril groups, respectively, were normotensive. The findings of this study are in agreement with other studies comparing the efficacy of ramipril and another ACE inhibitor in the treatment of hypertension.
The safety and efficacy of ramipril vs. enalapril in the treatment of hypertension was evaluated in a randomized, double-blind, multicenter trial.7 One hundred fifty-nine patients were enrolled and randomized to receive ramipril 2.5, 5, or 10 mg or enalapril 5, 10, or 20 mg for three to four weeks. Supine and standing blood pressures were reduced by 11.8 and 10.2 mmHg with ramipril 10 mg (P < 0.001) and 9.3 and 10.7 mmHg with enalapril 20 mg (P < 0.001). At the end of the four-week trial, patients in all six dosage groups had clinically and statistically significant reductions in blood pressure compared with baseline values, and the agents did not differ significantly with respect to their blood-pressure-lowering effects. Only results of comparisons of the ramipril group as a whole vs. the enalapril group as a whole should be considered. However, when comparing individual dosage groups, the sample size was too small to make reliable conclusions based on the results of the comparison.
The studies above reflect the results of the majority of similar studies conducted. The conclusions of these trials demonstrate that ramipril lowers blood pressure in hypertensive patients, has a long duration of action suitable for once-daily administration in most patients, and is well-tolerated. These results also demonstrate that ramipril is as effective as the other ACE inhibitors.
Heart failure post-myocardial infarction
Several ACE inhibitors on the Huntsville Hospital formulary are FDA-approved for use after a myocardial infarction. ACE inhibitors reduce afterload, preserve electrolytes, and reduce the ventricular enlargement that ensues in some patients after myocardial infarction. Ramipril also is FDA-approved for the treatment of stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction (AMI).
In a multicenter, double-blind, randomized, placebo-controlled study, ramipril was evaluated in 2,006 patients with AMI and clinical evidence of heart failure.8 Patients were randomly allocated to treatment with either placebo or ramipril on day three to day 10 after AMI. Patients with severe heart failure resistant to conventional therapy, and for whom the use of an ACE inhibitor was considered mandatory, were excluded. Follow-up was continued for a minimum of six months and an average of 15 months. Mortality from all causes was significantly lower for patients randomized to receive ramipril (170 deaths; 17%) than for those randomized to receive placebo (222 deaths; 23%). The observed risk reduction was 27% (P = 0.002). Analysis of prespecified secondary outcomes revealed a risk reduction of 19% for the first event in an individual patient — namely, death, severe/ resistant heart failure, myocardial infarction, or stroke (P = 0.008). This trial shows the survival benefit of ramipril use after AMI and is representative of other similar trials conducted with ramipril in this patient population.
Cardiovascular risk reduction
Most of Huntsville Hospital’s ACE inhibitors on formulary show some data for mortality benefit. Captopril and lisinopril have been shown to decrease mortality post-myocardial infarction, and enalapril has been shown to decrease mortality in patients with heart failure. Ramipril, however, is the only ACE inhibitor shown to reduce the risk of cardiovascular events including death in those at high risk for these events, regardless of whether they have heart failure.
The Heart Outcomes Prevention Evaluation (HOPE) study was a large, multicenter, randomized, placebo-controlled, 2x2 factorial design, double-blind study.2 It was conducted in 9,541 patients who were age 55 years or older and considered at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that was accompanied by at least one other cardiovascular risk factor. Patients were either normotensive or under treatment with other antihypertensive agents, and they were excluded if they had clinical heart failure or were known to have a low ejection fraction. This study was designed to examine the long-term effects of ramipril on the combined endpoint of myocardial infarction, stroke, or death from cardiovascular causes. The study results showed that ramipril 10 mg daily significantly reduced the rate of myocardial infarction, stroke, or death from cardiovascular causes, as well as the rates of the three components of the combined endpoint (see Table 3, below).
The secondary endpoints of this study also showed significant benefit for those receiving ramipril therapy. The ramipril group had significantly fewer revascularizations and complications related to diabetes. The group also had lower incidences of heart failure, cardiac arrest, worsening angina, and new diagnosis of diabetes. The study showed that ramipril is beneficial in a broad range of patients without evidence of left ventricular systolic dysfunction or heart failure who are at high risk for cardiovascular events.
This landmark study also demonstrates that ACE inhibitor therapy decreases the incidence of death and cardiovascular events in patients who are at high risk for these events but who do not have heart failure. Results of other studies have proven ACE inhibitors to be effective in preventing death in those with heart failure.
The magnitude of the benefit of treatment with ramipril was at least as large as that observed with other proven secondary measures, such as treatment with beta-blockers, aspirin, and lipid-lowering agents. In addition, the rapid and sustained response to ramipril and the continuing divergence in results between the ramipril group and the placebo group indicate that treatment for longer periods of time may yield even better results. The benefits of ramipril were observed among patients who were already taking a number of effective treatments, such as aspirin, beta-blockers, and lipid-lowering agents, indicating that inhibition of ACE offers an additional approach to the prevention of atherothrombotic complications. Only a small part of the benefit could be attributed to a reduction in blood pressure, because the majority of patients did not have hypertension at baseline, and the mean reduction in blood pressure with treatment was extremely small.9 The results of this study can be reliably used to make conclusions about ramipril therapy because of the study’s strong design. A significant weakness is that the baseline demographics of the treatment groups were not compared statistically, so there might have been differences in the treatment groups from the start of the study.
Congestive heart failure
The ACE inhibitors on the Huntsville Hospital formulary are FDA-approved for use in heart failure. These provide both hemodynamic and symptomatic improvement by decreased ventricular remodeling, anti-ischemic processes, and blunting of neurohormonal activation. Although ramipril is not FDA-approved for the treatment of heart failure, several studies suggest that it also may be beneficial in this disease state.
In a randomized trial, 15 patients with grade III New York Heart Association congestive heart failure were assigned to treatment with either captopril or ramipril.10 Both groups were similar with respect to baseline hemodynamic measurements. The group receiving ramipril showed hemodynamic changes comparable to the group receiving captopril on the seventh day of treatment. The stroke volume index increased by 20% vs. 21%, respectively, and the total peripheral resistance decreased by 13% vs. 20%, respectively. Hemodynamic improvement was more pronounced and comparable in both groups during exercise. The study concluded that ramipril is equally effective compared with captopril in the treatment of patients with severe congestive heart failure. However, this study was only for a short period of time with a small sample size, and no reliable conclusions can be drawn from these results. Most of the published trials comparing the efficacy of ramipril in the treatment of heart failure to other ACE inhibitors concluded that ramipril is equal in efficacy to the other ACE inhibitors, but they were limited by small sample sizes.
The clinical trials included above are only a few of the many published trials involving ramipril. This evaluation contains a representative sample of the ramipril trials available.
Ramipril has been evaluated for safety in more than 4,000 patients with hypertension. Of these, 1,230 patients were studied in U.S. controlled trials, and 1,107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in ramipril and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ramipril in U.S. placebo-controlled trials were headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last was more common in ramipril patients than in patients given placebo. Generally, the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 to 20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of U.S. patients treated with ramipril. The most common reasons for discontinuation were cough (1.0%), dizziness (0.5%), and impotence (0.4%). The side effects considered possibly or probably related to study drug that occurred in more than 1% of patients treated with ramipril are shown in Table 4, below.2
In placebo-controlled trials, there also was an excess of upper respiratory infection and flu syndrome in the ramipril group. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later one-year study, increased cough was seen in almost 12% of ramipril patients, with about 4% of these patients requiring discontinuation of treatment.2
In the Acute Infarction Ramipril Efficacy (AIRE) study, which evaluated the use of ramipril in patients after myocardial infarction, there were fewer patients with reported serious adverse events on ramipril (58%) than placebo (64%). Serious adverse events included the endpoints of the trial (death, progression to severe/resistant heart failure, reinfarction, and stroke), as well as possible adverse effects of treatment.1 Adverse reactions considered possibly/probably related to study drug that occurred in more than 1% of patients with heart failure treated with ramipril are shown in Table 5, below.2
Safety data in the HOPE trial, which evaluated cardiovascular risk reduction with ramipril, were collected as reasons for discontinuation or temporary interruption of treatment (see Table 6, below). The incidence of cough was similar to that seen in the AIRE trial. The rate of angioedema was the same as in previous clinical trials.
Side effects with ramipril are usually mild or transient. Cough is the most common adverse event reported in patients taking ACE inhibitors. It is a class effect, with no dose-response relationship.3 The incidence of cough with ramipril is comparable to that of the other ACE inhibitors. The adverse effect profiles of the ACE inhibitors are not significantly different enough to favor one ACE inhibitor over another.3 The results of the previously mentioned trials showed the overall frequency of adverse events to be similar in patients treated with ramipril and in those treated with placebo. In the AIRE trial, renal failure occurred with a similar frequency in the two groups. Angina, which was thought to worsen in some patients prescribed an ACE inhibitor, was reported as an adverse event in 18% of patients taking ramipril and 17% of patients taking placebo. This shows that ramipril also is generally well-tolerated.
Ramipril is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an ACE inhibitor.6 Like other ACE inhibitors, ramipril is contraindicated in pregnancy.
Drug interactions with the ACE inhibitors are associated mostly with the class as a whole.4 Like the other ACE inhibitors, ramipril interacts with diuretics, especially potassium-sparing diuretics, potassium supplements, and lithium, and demonstrates a drug interaction profile similar to those of the other ACE inhibitors.
The cost to the hospital of oral ACE inhibitor therapy ranges from approximately $2.75 to $6.75 per week for most regimens, depending on drug and dose.11 Ramipril costs to the hospital are in the middle of this range. Enalapril and fosinopril are slightly more expensive than ramipril in equivalent doses, while lisinopril and quinapril are slightly less expensive. Captopril tends to cost considerably less than the other drugs in this class.
Conclusions and recommendations
Captopril, enalapril/enalaprilat, fosinopril, and lisinopril are the current formulary ACE inhibitors at the Huntsville Hospital System.
Based on the evidence provided in this formulary evaluation, ramipril should be added to the formulary. Ramipril is the only ACE inhibitor shown to be beneficial in a broad range of patients without evidence of left ventricular systolic dysfunction or heart failure who are at high risk for cardiovascular events. Ramipril has been shown to reduce the risk of cardiovascular events in high-risk patients; this information currently is unavailable for the other ACE inhibitors. Most patients are in the hospital for a short time, so the ACE inhibitor they receive during their stay is not likely to impact long-term therapeutic effects; however, many patients are discharged on the ACE inhibitor that they received during their hospital stay. This warrants the need for ramipril to be added to the formulary. The adverse effect profile and drug interaction profile are comparable to that of other ACE inhibitors on formulary; the cost is slightly higher.
1. Ramipril (monograph in electronic version). MICROMEDEX Healthcare Series. Englewood, CO: MICROMEDEX; 2001.
2. Monarch Pharmaceuticals. Ramipril (Altace) product information. Bristol, TN; 2000.
3. Knowles G. ACE inhibitor formulary proposal. Presented to Huntsville (AL) Hospital Pharmacy and Therapeutics committee; 1999.
4. Kaplan N, Sproul L, Mulcahy W. Large prospective study of ramipril in patients with hypertension. CARE Investigators. Clin Ther 1993;15:810-818.
5. Villamil A, Cairns V, Witte P, et al. A double-blind study to compare the efficacy, tolerance and safety of two doses of the angiotensin-converting enzyme inhibitor, ramipril, in mild-to-moderate primary hypertension. Am J Cardiol 1987;59:110-114.
6. Witte P, Walter U. Comparative double-blind study of ramipril and captopril in mild-to-moderate essential hypertension. Am J Cardiol 1987;59:115-120.
7. Ruddy M, Mroczek W. Comparison of ramipril and enalapril in patients with essential hypertension. Pharmacotherapy 1993;13:224-228.
8. Anonymous. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy Study Investigators. Lancet 1993;342:821-828.
9. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-153.
10. Manthey J, Osterziel K, Rohrig N, et al. Ramipril and captopril in patients with heart failure: Effects on hemodynamics and vasoconstrictor systems. Am J Cardiol 1987; 59:171-175.
11. Hall C. Personal communication. Pharmacy buyer. Huntsville (AL) Hospital Systems Pharmacy; September 2001.